Protein quality control mechanisms are required for normal cellular health to prevent disease and avoid premature senescence. Unique mutant proteins are substrates of these pathways, are recognized by protein quality control pathway components and typically degraded by the proteasome. Proteins with subtle missense mutations can retain function yet degradation by these pathways can underlie pathogenesis. The molecular and physical basis of protein quality control substrate recognition are poorly understood, especially for soluble cytosolic proteins. This application proposes to use a powerful multi disciplinary approach to define novel proteins in the protein quality control pathway and elucidate the physical and structural basis of substrate recognition.